Compounds and pharmaceutical compositions for treating disorders associated with the 5-ht1a and 5-ht2a receptors

ABSTRACT

Alkyl-piperazine-phenyl 4 (3H)-quinazolinones compounds of general formula (I) below are provided that are pharmacologicaly active and able to act on the 5-HT1A and 5-HT2A serotonin receptors in a manner that promotes the control, relief or cure of disorders associated with these receptors, and pharmaceutical compositions containing the compounds for the treatment of disorders associated with these receptors. These compounds and their pharmaceutical compositions are useful in the treatment of conditions such as depression, anxiety, phobias, addictions, aggressiveness, impulsiveness, panic, psychotic, eating and sleep disorders, obsessive-compulsive disorder and female sexual dysfunctions, including loss of sexual desire, inhibition of sexual desire and absence of sexual desire, among other disorders associated with these receptors.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of U.S. patentapplication Ser. No. 13/824,063, having a filing date of Mar. 19, 2013,which is a National Stage Application of PCT/BR2011/000374, filed Sep.22, 2011, all of said applications incorporated herein by reference.

FIELD OF THE INVENTION

This invention is related to the alkyl-piperazine-phenyl 4(3H)-quinazolinone compounds, which are pharmacologicaly active and ableto interact with the 5-HT_(1A) and 5-HT_(2A) serotonin receptorspromoting the control, relief or cure of disorders associated with thesereceptors and pharmaceutical compositions containing the compounds. Thisinvention is also related to the use of these compounds in the treatmentof depression and anxiety disorders, phobias, addictions,aggressiveness, impulsiveness, panic, eating, sleep and psychoticdisorders, obsessive-compulsive disorder, female sexual dysfunctions,among others disorders associated with the 5-HT_(1A) and 5-HT_(2A)serotonin receptors.

BACKGROUND OF THE INVENTION

Selective Serotonin Reuptake Inhibitors (SSRI) constitute the class ofmedications that are currently most widely used for the treatment ofdepression and anxiety disorders, obsessive-compulsive disorder,phobias, social phobia and panic.

These drugs act on the serotonin transporter, a protein integrated withthe membrane whose function is to transport theneurotransmitter—serotonin—from the synaptic spaces to the interior ofthe pre-synaptic neurons. Its inhibition by the SSRIs triggers anincrease in the serotonin concentration in the synapses, resulting ingreater availability of this neurotransmitter for binding with theserotonin receptors of the contiguous neurons, with the consequentpropagation of the nerve impulse. Although the SSRIs extend theavailability of serotonin in the synapses, this neurotransmitter is notspecific for binding with the different existing serotonin receptors.

At the moment, seven families or populations of serotonin receptors areknown, classified from 5-HT₁ to 5-HT₇ on the basis of their differentstructural and operating characteristics. Multiple subpopulations orsubtypes (homologous types and conjugated variants) exist for each ofthese families. While some subtypes have been targeted by many studiesallowing their characterization in structural and functional terms, thefunction of other subtypes have not yet been fully elucidated(Psychopharmacology—4th Generation—Serotonin Receptors, Subtypes andLigands—Glennon et al, available at:http://www.acnp.org/g4/GN401000039/Ch039.html).

In addition to interacting with the serotonin transporter, serotonininteracts indistinctly with all the populations and the respectivesubpopulations of the serotonin receptors. If on the one hand theincrease on the concentration of serotonin has a positive therapeuticeffect that is appropriate for treating certain dysfunctions, on theother side this increase prompts the appearance of undesired sideeffects, probably resulting from the indiscriminate activation ofnon-specific receptors that are not related to the disorders beingtreated.

Several studies describe the importance of the 5-HT_(1A) agonism, withthe activation of these receptors being particularly relevant for thetreatment of depression and anxiety disorders, phobias, panicimpulsiveness, obsessive-compulsive disorder, among others. Some drugshave been developed, specifically targeting these receptors. This is thecase of buspirone and tandospirone which, although serving as partialagonists, target only the 5-HT_(1A) receptors, not presenting anysignificant affinity for other serotonin receptors.

Although these drugs target the 5-HT_(1A) receptors whose activation isacknowledged as important in the treatment of these various disorders,they are not rated as first choice drugs, mainly because their effectsin the treatment of depression and other associated disorders aresignificantly less than those presented by the SSRIs. Among thehypotheses presented to explain this behavior, or deficiency ofactivity, is the fact that they act as partial agonists with thesereceptors. In fact, the mechanism of action of buspirone occurs throughthe agonism of the pre-synaptic 5-HT_(1A) receptors, while it actstogether with the post-synaptic 5-HT_(1A) receptors as a partial agonist(The American Psychiatric Publishing Textbook of Psychopharmacology, 4thEdition, Chap. 25—Buspirone and Gepirone—edited by Alan F. Schatzbergand Charles B. Nemeroff).

Recent studies indicate that 5-HT_(1A) and 5-HT_(2A) receptors areparticularly involved in disorders related to depression and anxiety.While the agonism of the 5-HT_(1A) receptors seems to have a favorabletherapeutic effect in the treatment these disorders, the antagonism ofthe 5-HT_(2A) receptors seems to be responsible for triggering a similareffect. Thus, it is believed that the therapeutic effect arising fromthe agonism of the 5-HT_(1A) receptors is partially neutralized shouldthe substance promote in parallel the agonism of the 5-HT_(2A)receptors, indicating the possible existence of a functional antagonismbetween the two receptors (Marek et al in Neuropsychopharmacology (2003)28: 402-412; Celada et al in J. Psychiatry Neurosci. (2004) 29 (4):252-265).

The long latency period between the start of the treatment and theappearance of the initial effects noted in patients being treated withthe SSRIs, may be associated at least partially with the increasedconcentration of serotonin available to the 5-HT_(2A) receptors. It isalso suspected that the agonism of the 5-HT_(2A) receptors isresponsible for some of the side effects attributed to the SSRIs,including sexual dysfunction.

Recently, a drug under development drew fresh attention to the jointmodulation of the 5-HT_(1A) and 5-HT_(2A) serotonin receptors, when itsdual mechanism of action triggered promising effects in the treatment offemale sexual dysfunctions. Although the mechanism of action of thisdrug has not yet been fully explained, the participation of these tworeceptors in female sexual functioning had already been addressed byMeston et al (Current Opinion in Urology (2001) 11: 603-609), whomentioned that there is evidence that the activation of the 5-HT₂receptors would hamper sexual functioning, while the stimulation of the5-HT_(1A) receptors would facilitate this, which might be the reason whythe SSRIs produce side effects.

In view of the matters set forth above, the quest for drugs that couldinteract simultaneously with the 5-HT_(1A) and 5-HT_(2A) receptors maywell offer better control or more effective treatment for severaldisorders, which could be accompanied by a briefer latency period forthe appearance of the therapeutic effect and also a reduction,moderation or elimination of the side effects that are noted when theSSRIs are employed, being agents that, due to their mechanism of action,trigger and increase in the serotonin concentration that acts in anon-selective manner on all the serotonin receptors.

Several pharmacological properties are attributed to substancesbelonging to the quinazolinone class. More specifically, with regard tothe alkyl-phenylpiperazine-4 (3H)-quinazolinones, derivatives of thistype were described in the state of the art presenting sedative,hypnotic, anti-hypertensive and anti-inflammatory properties.

U.S. Pat. No. 3,047,462 describes 4 (3H)-quinazolinones, in addition toother 4-quinazolines, which present anti-inflammatory properties.

U.S. Pat. No. 3,073,826 describes 3-pyrrolidylmethyl-4(3H)-quinazolinones, which present anti-inflammatory properties.

U.S. Pat. Nos. 3,086,910, 3,448,109 and 3,928.354 describe substituted 4(3H)-quinazolinones, 2-methyl and 3-aryl, which are endowed withhypnotic, muscle relaxant and anti-spasmodic activities. The substancesdescribed in these documents present ample structural similarity withmethaqualone and its derivatives, which are hypnotic agents whose salewas suspended due to their high potential for developing dependency andabuse.

U.S. Pat. No. 3,231,572 describes substituted 4 (3H) quinazolinones,2-methyl or phenyl and substituted 3-alkyl-piperazinyl-phenyl that areuseful as anti-inflammatory agents or sedative agents. The testsconducted with the compounds described in this document demonstratedthat these substances are endowed with hypotensive and anti-histaminicproperties, not presenting any sedative properties (Journal of OrganicChemistry (1969), 12: 936-938, Shin Hayao et al). U.S. Pat. No.3,984,555 describes substituted aryl-piperazinyl-alkyl-4 (3H)quinazolone derivatives that have hypotensive, anti-histaminic andanalgesic properties. Most of the compounds synthesized in this documentare di-substituted 4 (3H)-quinazolinones 6,7-methoxy, bound in position2 of the quinazolinones by an alkyl chain of one, two or three carbonatoms with the piperazine-phenyl portion substituted by 2, 3 or 4methyl, methoxy, chlorine or fluor. The authors affirm that thesecompounds are endowed with properties that are particularly useful inthe treatment of hypertension.

U.S. Pat. No. 4,841,051 describes substituted 4 (3H)-quinazolinonesethyl-piperazine-phenyl-2-ethoxy that have an activity blocking the alreceptors, being useful in the treatment of hypertension.

Compounds belonging to the quinazolinedione class were described in U.S.Pat. Nos. 3,274,194, 3,726,979, 4,335,127, 4,578,465 and 5,264,438.

U.S. Pat. No. 3,274,194 describes substituted 2,4(1H,3H)-quinazolinediones-3-derivatives, which are useful asanti-inflammatory and sedative agents. This document describespelanserin, a hypotensive agent that was subsequently discovered to bean antagonist of the 5-HT₂ receptors without presenting affinity for the5-HT_(1A) receptors. The description that these compounds are serotoninantagonists is presented in U.S. Pat. No. 3,726,979.

U.S. Pat. No. 4,335,127 describes substituted2,4-(1H,3H)quinazolinediones-3-alkyl-piperidine derivatives as compoundsthat are powerful serotonin antagonists. Among the compounds moststudied described in this Patent are ketanserin, altanserin andbutanserin. All these compounds are endowed with high affinity for the5-HT_(2A) receptors, without presenting any affinity for the 5-HT_(1A)receptors.

U.S. Pat. No. 4,578,465 describes substituted2,4-(1H,3H)quinazolinediones-alkyl-methoxy-phenyl-piperazine compounds,with serotonin antagonist properties and able to block thealpha-adrenergic receptors.

U.S. Pat. No. 5,264,438 describes derivatives belonging to the 2,4(1H,3H)-quinazolinedione family, which are endowed with serotoninantagonist properties, acting particularly as antagonists of the 5-HT₂receptors, in addition to presenting antagonist properties together withthe α₁-adrenergic receptors and agonists together with the dopaminergicreceptors.

Other compounds presenting serotonin activity and the receptorsinvolved, without belonging to the quinazolinone or quinazolinedioneclasses, were described in U.S. Pat. No. 3,717,634, GB 2,023,594 and4,203,98.

U.S. Pat. No. 3,717,634 describes N-heteroaryl-cyclic-piperazinyl-alkylcompounds derived from 8-azaspyro[4,5] decane-7,8-dione, which areendowed with activity together with the 5-HT_(1A) receptors, with themain representative being buspirone, an agent with anxiolyticproperties. This substance acts as a partial agonist on the 5-HT_(1A)receptors, not presenting interaction or affinity for the 5-HT_(2A)receptors.

GB Patent 2,023,594 describes substituted4-(3-trifluoro-methyl-thiophenyl)-piperazines-1-alkyl which may havesubstitutions binding to the alkyl group. The compounds describedpresent activity with the central nervous system.

U.S. Pat. No. 4,203,986 describes substituted m-trifluoromethylphenylpiperazines N-alkyl and/or cycloalkyl presenting activity with thecentral nervous system and the cardiovascular system, associated withsedative, tranquilizing and anti-tussive properties. Among the documentsthat describe compounds with selective affinity for the 5-HT_(1A) and5-HT_(2A) receptors are U.S. Pat. Nos. 5,576,318, 6,586,435 and6,281,218 that describe N-substituted benzimidazolones by substitutedalkyl mono and di-phenylpiperazines, with these compounds presentingaffinity for the 5-HT_(1A) and 5-HT_(2A) receptors, being useful for thetreatment of central nervous system disorders, such as the treatment ofdepression, anxiety, neurodegenerative diseases and psychoses, forexample, among others. The best compound known compound in this class ofsubstances described in these documents is flibanserin, a drug whoseclinical trials showed that it was not efficient for the treatment ofdepression and that is currently undergoing clinical trials for thetreatment of hypoative sexual desire disorder and other female sexualdysfunctions.

Kleven et al (Journal of Pharmacology and Experimental Therapeutics(1997), 282: 747-759) describe other substances presenting affinitiesfor the 5-HT_(1A) and 5-HT_(2A/2C) receptors and that may be useful inthe treatment of anxiety and depression disorders. These substances,initially proposed in U.S. Pat. Nos. 4,797,489, 5,166,157, 5,565,455,4,604,397 and 4,721,787, are at various phases of studies for thetreatment of disorders related to the modulation of these receptors.

Although there are theories defending the possible clinical advantagesof developing drugs directed towards the 5-HT_(1A) and 5-HT_(2A)receptors, the substances developed so far and presenting this activityprofile have not yet demonstrated the clinical efficacy required fortheir approval by the regulatory authorities, in addition todemonstrating effects fall well below the effects obtained with theSSRIs.

Surprisingly, the current inventors synthesized a particular family ofcompounds of the substituted 4(3H)-quinazolinones-alkyl-piperazine-phenyl type, whose representativespresent a high affinity for the 5-HT_(1A) and 5-HT_(2A) receptors andthus may be useful in the treatment or cure of several disordersassociated with these receptors.

So far, the 4 (3H)-quinazolinones similar to those now describeddemonstrated that they are endowed with anti-hypertensive and/oranti-histaminic properties, with no circumstantial evidence indicatingthat they might be useful for the treatment of disorders attributed tomodulations of the serotonin system, more specifically acting on the5-HT_(1A) and 5-HT_(2A) receptors.

Studies conducted with the compounds addressed by this inventiondemonstrated that they gather together the structural characteristicsthat are appropriate for binding with the 5-HT_(1A) and 5-HT_(2A)receptors, with these properties related to the adequate size of thealkyl chain for linking the 4 (3H)-quinazolinone portion with thephenylpiperazine portion, associated with the need for the presence ofsteering groups that are appropriate and correctly oriented in thephenyl portion of the phenylpiperazine to promote anchoring of theappropriate confirmation of these compounds to these receptors.

Thus, this invention addresses substituted 4(3H)-quinazolinones-alkyl-piperazine-phenyl compounds that have anaffinity for the 5-HT_(1A) and 5-HT_(2A) serotonin receptors, with thesecompounds being useful in the treatment of persons affected by disordersassociated with these receptors, such as depression, anxiety, phobias,addictions, aggressiveness, impulsiveness, panic, eating, sleep andpsychotic disorders and obsessive-compulsive disorder in addition tobeing able to act on the heat regulation mechanism, presentingneuroprotective properties and also able to act on or assist with thetreatment of female sexual dysfunctions, which encompass hypoativesexual desire disorder, sexual aversion disorder, female sexualexcitation disorder, and the loss, inhibition or absence of sexualdesire.

BRIEF DESCRIPTION OF THE DRAWING FIGURE

FIG. 1 refers to a graph obtained from the responses to the in vivoefficacy test for the inventive compounds presented in Examples 1 and 2,and the comparative compound constituting the state of the art. Thequantified values correspond to the number of observations conducted onthe parameters: head twitches (HT), fore paw treading (FPT), flat bodyposture (FBP), hind-limb splay (HLS), lower lip retraction (LLR) andspontaneous tail flicks (STF).

DESCRIPTION OF THE INVENTION

This invention is related to the general formula compounds (I) shownbelow:

where,

n=2;

R₁ is hydrogen or ethyl and R2 is selected from the group consisting of3-trifluormethylphenyl, 2-chlorophenyl, 2-methylphenyl,2,3-dimethylphenyl, 2-cyanophenyl, 2-methoxyphenyl and 2-ethoxyphenyl,which are useful in the treatment of disorders associated with the5-HT_(1A) and 5-HT_(2A) serotonin receptors.

The specific preferred compounds in the general formula (I) are:

-   3-(2-(4-(3-(trifluoromethyl) phenyl) piperazine-1-yl)ethyl)    quinazoline-4 (3H)-one;-   3-(2-(4-o-tolylpiperazine-1-yl)ethyl)quinazoline-4 (3H)-one;-   3-(2-(4-(2,3-dimethylphenyl)piperazine-1-yl)ethyl) quinazoline-4    (3H)-one;-   3-(2-(4-(2-chlorophenyl)piperazine-1-yl)ethyl)quinazoline-4    (3H)-one;-   3-(2-(4-(2-cyanophenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one;-   3-(2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl)quinazoline-4    (3H)-one;-   2-ethyl-3-(2-(4-(2-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)    quinazoline-4 (3H)-one;-   3-(2-(4-(2,3-dimethylphenyl)piperazine-1-yl)ethyl)-2-ethylquinazoline-4    (3H)-one;-   3-(2-(4-(2-chlorophenyl)piperazine-1-yl)ethyl)-2-ethylquinazoline-4    (3H)-one;-   2-ethyl-3-(2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl)    quinazoline-4 (3H)-one;-   3-(2-(4-(2-ethoxyphenyl)piperazine-1-yl)ethyl)-2-ethylquinazoline-4    (3H)-one.

The general formula compounds (I) above are basic in nature, being ableto form salts for addition with various organic and inorganic acids.Thus, this invention also encompasses the appropriate pharmaceuticalsalts of the general formula compounds (I), which may be formed withnon-toxic inorganic acids or organic acids.

The general formula compounds (I), or their appropriate pharmaceuticalsalts, may be administered alone or in the form of a pharmaceuticalcomposition. Thus, this invention also has as an objective apharmaceutical composition for treating disorders associated with the5-HT_(1A) and 5-HT_(2A) receptors, encompassing at least one of thegeneral formula compounds (I) in a therapeutically efficacious quantity,or its appropriate pharmaceutical salts, associated with at least oneappropriate pharmaceutical excipient.

This invention is also related to the use of the general formulacompounds (I) or their appropriate pharmaceutical salts for thetreatment or the prevention of disorders associated with the 5-HT_(1A)and 5-HT_(2A) receptors, such as: depression, anxiety, phobias, panic,addictions, aggressiveness, impulsiveness, eating disorders, sleepdisorders, obsessive-compulsive disorder, psychotic disorders, disordersinvolving the heat regulation mechanism, and as a neuroprotetormedication as well as for female sexual dysfunctions, which encompasshypoative sexual desire disorder, sexual aversion disorder, femalesexual excitation disorder, and the loss, inhibition or absence ofsexual desire.

Another objective of this invention is the use of the general formulacompounds (I) or their appropriate pharmaceutical salts it may be usedto prepare medication for the treatment and/or the prevention ofdisorders associated with the 5-HT_(1A) and 5-HT_(2A) receptors, suchas: depression, anxiety, phobias, panic, addictions, aggressiveness,impulsiveness, eating disorders, sleep disorders, obsessive-compulsivedisorder, psychotic disorders, disorders involving the heat regulationmechanism, and as a neuroprotetor medication as well as for femalesexual dysfunctions, which encompass hypoative sexual desire disorder,sexual aversion disorder, female sexual excitation disorder, and theloss, inhibition or absence of sexual desire.

This invention also has as an objective a method for treating anindividual mammal, including human beings, which consists ofadministering a therapeutically efficacious quantity of a compound ofthe formula (I), or its appropriate pharmaceutical salts, for thetreatment of disorders selected from the group consisting of:depression, anxiety, phobias, panic, addictions, aggressiveness,impulsiveness, eating disorders, sleep disorders, obsessive-compulsivedisorder, psychotic disorders, disorders involving the heat regulationmechanism, female sexual dysfunctions, which encompass hypoative sexualdesire disorder, sexual aversion disorder, female sexual excitationdisorder, and the loss, inhibition or absence of sexual desire, and alsoits use as a neuroprotector.

The general formula compounds (I) of this invention may be preparedthrough various routes using the usual synthesis methods. In thisinvention, these compounds were prepared through the stages presented inDiagram 1 below.

Pursuant to Diagram 1, the general formula compounds (I) where R₁ issubstituted by hydrogen and R2 is as described previously, were preparedfrom anthranilic acid, using ethyl orthoformate and monoethanolamine forthe formation of the intermediate 3-(2-hydroxyethyl)quinazoline-4(3H)-one. The reaction of this intermediate with the thionyl chlorideresulted in the formation of the chlorated derivative, which wassubsequently condensed with the substituted piperazine phenyl resultingin the desired compounds.

The general formula compounds (I) where R₁ is substituted ethyl and R2is as described previously, were prepared that was submitted to reactionwith propanoyl chloride with the anthranilic acid generating2-propionamide benzoic acid. The reaction of this intermediate with theacetic anhydride resulted in the substituted benzoxazinone-2-ethyl. Thereaction was submitted to reaction with monoethanolamine for theformation of the intermediate 2-ethyl-3-(hydroxymethyl)quinazoline-4(3H)-one. A reaction of this intermediate with thionyl chloride resultedin the chlorated derivative, which was subsequently condensed with thesubstituted piperazine phenyl, resulting in the desired compounds.

Although the general formula compounds (I) were prepared using thereaction stages described in Diagram 1, other synthetic approaches maybe used to obtain them, without adversely affecting the outcome.

The synthetic route used proved to be quite practical for obtaining thecompounds addressed by this invention, which may be easily isolated andpurified.

Examples of synthesizing the compounds are described in Examples 1 to11.

The general formula compounds (I) of this invention are endowed with abasic nature and may form salts for addition with various organic andinorganic acids.

Examples of organic acids appropriate for use in the formation of theappropriate pharmaceutical salts of the general formula compounds (I)are: fumaric, acetic, propionic, benzoic, ascorbic, pamoic, succinic,oxalic, salicylic, maleic, tartaric, citric, lactic, malic, stearic,palmitic, benzenesulfonic, p-toluenesulfonic, methanesulfonic,ethanesulfonic, aspartic, mandeic, cinnamic, glycolic, gluconic,glutamic and p-aminobenzoic, among others.

Examples of inorganic acids appropriate for use in the formation of theappropriate pharmaceutical salts of the general formula compounds (I)are: hydrochloric, hydrobromic, sulfuric, phosphoric and nitric, amongothers.

The pharmaceutical salts of the general formula compounds (I) may beprepared through the usual procedures described in the state of the art,using the conditions and solvents appropriate for their formations. Theacid salts for adding to the compound addressed by this invention may beeasily prepared through treating the base compound with a molar quantityequivalent to or in excess of the selected acid, using organic solvents,blends of organic solvents, and blends of organic solvents and water.

The compounds addressed by this invention and/or its appropriatepharmaceutical salts may be administered alone or in the form of apharmaceutical composition. When administered in the form of apharmaceutical composition, the compounds addressed by this invention orthe appropriate pharmaceutical salts thereof will be associated with atleast one conventional or appropriate pharmaceutical excipient.

Pursuant to this invention, a conventional or appropriate pharmaceuticalexcipient is deemed to be any substance other than the activepharmaceutical ingredient, that has been appropriately assessed in termsof its safety and has been intentionally included in a pharmaceuticaldosing form.

The selection of excipients to be used or preparing pharmaceuticalcompositions is generally undertaken by taking into consideration thetype of administration pathway, the physical and chemical compatibilityof the excipient with the active ingredient, the manner of preparing thepharmaceutical presentation and the effects on its efficacy. Theseexcipients are widely known in the state of the art and are described inthe literature (Handbook of Pharmaceutical ManufacturingFormulations—Vol. 1 a 6—2004—Sarfaraz K. Niazi—CRC Press and Remington'sPharmaceutical Sciences, Mack Publishing), widely used by technicalexperts in the matter.

Pharmaceutical excipients usually classified or sub-classified on thebasis of the function that they perform in the pharmaceuticalcompositions and/or in their manufacturing technique. They may be calleddiluting agents, binding agents, breakdown or anti-clumping agents,lubricants, suspension agents, thickening agents, solvents, surfactants,slip agents, anti-clumping or flow agents, coating agents, plastifyingagents, sweeteners, isotonicity agents, colorants, conservants,antioxidants, pH control or modification agents, complexing agents usedto mask flavor, improve solubility, promote formulation stability, andmodulate bioavailability, in addition to chelating, aromatizing andflavorizing agents.

Diluting agents are pharmaceutical excipients included in solid dosageforms, such as tablets, capsules, pills, pellets, powders and granules,in order to increase the volume or the weight of the type of dosage.They also may be used in liquid and semi-solid pharmaceutical forms forthe same purpose. Examples of diluting agents appropriate for thepreparation of pharmaceutical compositions of this invention include butare not limited to: calcium carbonate, calcium phosphates, calciumsulfate, microcrystal cellulose, powdered cellulose, dextrins, dextrose,fructose, kaolin, anhydrous and/or monohydrated lactose, maltose,sorbitol, assorted starches (maize, wheat, potato, tapioca),pre-gelatinized starch, saccharose and sugar.

Binding agents are pharmaceutical excipients that are included in theformulations in order to ensure easier clumping of powders into granulesduring the blending (or granulation) stage, using water as a granulationfluid, or hydro-alcohol mixtures or other solvents. Binding agents mayalso be used in dry blending processes where no fluids are required.Examples of binding agents appropriate for the preparation of thepharmaceutical composition of this invention include but are not limitedto: acacia gum, alginic acid, ammonium methacrylate copolymer, carbomercopolymer or homopolymer or interpolymer, starches (maize, wheat,potato, tapioca), microcrystal cellulose, methyl cellulose, ethylcellulose, hydroxypropylmethyl cellulose, dextrin, maltodextrin,maltose, saccharose, gelatin, glucose, guar gum and povidone.

Breakdown or anti-clumping agents are pharmaceutical excipients that canspeed up the breakdown or dissolution of the formulation when in contactwith biological fluids. Examples of breakdown or anti-clumping agentsappropriate for the preparation of the pharmaceutical composition ofthis invention include but are not limited to: alginic acid, starches,sodium alginate, sodium croscaramelose, sodium glycolate, sodiumcarboxymethyl cellulose, microcrystal cellulose and crospovidone.

Lubricants are excipients that reduce friction among the particles inthe formulations and also lessen the friction between the particles andthe walls of the equipment used to prepare them. Examples of lubricantsappropriate for the preparation of the pharmaceutical composition ofthis invention include but are not limited to: calcium stearate,magnesium stearate, zinc stearate, mineral oil, polyethylene glycol,sodium lauryl sulfate, sodium stearyl fumarate, starch, stearic acid,talc and type I hydrogenated vegetable oil.

Suspension agents and thickening agents are excipients used informulations to ensure the stability of dispersed systems (for example,suspensions and emulsions), in order to reduce particle sedimentationspeed or to lessen the fluidity of liquid formulations. Examples ofappropriate suspension agents and thickening agents for preparing thepharmaceutical composition of this invention include but are not limitedto: acacia gum, agar, alginic acid, aluminum monostearate, bentonite,carbomer, copolymer carbomer, homopolymer carbomer, interpolymercarbomer, calcium or sodium carboxymethyl cellulose, carrageenan,microcrystal cellulose, dextrin, guar gum, gellan gum, hydroxyethylcellulose, hydroxypropylcellulose, methyl cellulose, aluminum magnesiumsilicate, pectin, polyethylene oxide, polyvinyl alcohol, povidone,propylene glycol alginate, sodium alginate, silicon dioxide, colloidalsilicon dioxide, starches (maize wheat, potato, tapioca), tragacanth gumand xanthan gum.

Solvents are excipients employed to dissolve other substances whenpreparing liquid, semi-solid and solid compositions, used for the latterin order to ensure easier blending and/or to provide a blend with ahomogeneous concentration of the active pharmaceutical ingredient orsome other excipient. Examples of solvents appropriate for thepreparation of the pharmaceutical composition of this invention includebut are not limited to: water, ethanol, isopropanol, plant oils (maize,cotton, sesame, soy), mineral oil, glycerin, sorbitol and oleic acid.

Surfactants are also known as surface tension modulation agents, and areexcipients with assorted functions, used as emulsifiers, humectantsand/or solubilization agents. Examples of surfactants appropriate forthe preparation of the pharmaceutical composition of this inventioninclude but are not limited to: benzalkonium chloride, benzethoniumchloride, cetylpyridinium chloride, nonoxynol 9, octoxynol 9, polyoxyl50 stearate, polyoxyl 10 oleyl ether, polyoxyl 20 cetostearyl ether,polyoxalate 35 ricin oil, hydrogenated polyoxalate 40 ricin oil,polyoxyl 40 stearate, polyoxyl lauryl ether, polyoxyl stearyl ether,polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, sodiumcetoestearyl sulfate, sodium lauryl sulfate, sorbitan monolaurate,sorbitan monoleate, sorbitan monoplamitate, sorbitan sesquioleate,sorbitan trioleate, cetyl alcohol, oleyl alcohol, poloxamer, propyleneglycol monostearate, carbomer copolymer or interpolymer, cholesterol,monoethanolamine, diethanolamine, triethanolamine, diethylene glycolstearates, sodium docusate, ethylene glycol stearates, glyceryldistearates, glyceryl monolinoleate, glyceryl monooleate, glycerylmonostearate, lanolin alcohols, lecithin, mono and diglycerides, sodiumstearate, stearic acid and emulsifying wax.

Flow agents, anti-clumping or slip agents are excipients used informulations to promote flows and reduce clumping in solids conductionfunnels during powder flows and processing. Examples of flow agents,anti-clumping or slip agents appropriate for the preparation of thepharmaceutical composition of this invention include but are not limitedto: calcium silicate, magnesium silicate, colloidal silicon dioxide andtalc.

Coating agents are excipients that may be used with various functions,including masking unpleasant flavors or odors, controlling drug releasespeed, enhancing appearance, easier swallowing and controlling therelease of the drug in the digestive tract (for example entericcoating). Examples of coating agents appropriate for the preparation ofthe pharmaceutical composition of this invention include but are notlimited to: ammonium methacrylate copolymer, sodium carboxymethylcellulose, cellulose acetate phthalate, cellulose acetate, copovidone,ethyl cellulose and its aqueous dispersions, gelatin, pharmaceuticalvarnishes, hydroxypropyl cellulose, hydroxypropylmethyl cellulose,hydroxypropyl methylcellulose acetate succinate, hydroxypropylmethylcellulose phthalate, maltodextrin, methacrylic acid copolymer and itsdispersions, methyl cellulose, polyethylene glycol, polyvinyl acetatephthalate, shellac, modified pre-gelatinized starch, saccharose,titanium dioxide, carnauba wax and microcrystal wax.

Plastifying agents are excipients added to other agents in order toendow them with greater plasticity and resilience (elasticity). They areimportant components for conferring the physical properties required bypolymer systems. Examples of plastifying agents appropriate for thepreparation of the pharmaceutical composition of this invention includebut are not limited to: acetyl tributyl citrate, acetyl triethylcitrate, ricin oil, diacetylated monoglycerides, dibutyl sebacate,sorbitol, dextrin, diethyl phthalate, glycerin, polyethylene glycol,polyethylene glycol monomethyl ether, propylene glycol, benzyl benzoate,triacetin, tributyl citrate, triethyl citrate and chlorobutanol.

For parenteral administration, it is normal to use isotonic solutions,meaning solutions with osmotic pressure similar to the tissues withwhich they come into contact, in order to avoid hemolyses, reducing painand the discomfort of administration. Examples of isotonicity agentsfrequently used to ensure the isotonicity of the pharmaceuticalcomposition of this invention include but are not limited to: dextrose,glycerin, manitol, sodium chloride, and potassium chloride.

Sweeteners are agents used to mask unpleasant flavors and sweeten oralformulations. Examples of sweeteners appropriate for the preparation ofthe pharmaceutical composition of this invention include but are notlimited to: acesulfame potassium, aspartame, acesulfame aspartame salt,dextrates, dextrose, fructose, galactose, maltitol, maltose, manitol,saccharine, calcium saccharine, sodium saccharine, sorbitol, sucralose,saccharose, sugar and tagatose.

The scope of the composition addressed by this invention alsoencompasses pharmaceutical colorants that are included in the dosingforms, in order to endow each medication with a distinct appearance,ensuring that it is easy to distinguish a specific formulation amongformulations with similar physical aspects. Examples of pharmaceuticalcolorants appropriate for use in the composition of this inventioninclude: red ferric oxide, yellow ferric oxide, ferric oxide blends,caramel, titanium dioxide, FD&C colorants and D&C colorants.

Depending on the administration pathway and the physical and chemicalproperties inherent to the compounds addressed by this invention,substances may be added to the pharmaceutical composition prepared withthese compounds that can stabilize, preserve, prevent and/or avoid thepremature degradation of its ingredients. These additional excipientsmay act as antioxidants, conservants, pH regulators or modifiers.Examples of excipients used with these properties that are appropriatefor the preparation of the pharmaceutical composition addressed by thisinvention include but are not limited to: ascorbic acid, sorbic acid,sodium meta bisulfite, alpha-tocopherol, methylparaben, propylparaben,butylparaben, sodium sulfite, butylated hydroxytoluene (BHT), butylatedhydroxyanisole (BHA), phenol, benzyl alcohol, benzalkonium chloride,benzethonium chloride, cetylpyridinium chloride, benzoic acid, sodiumbenzoate, sodium propionate, boric acid and the pH control agents, thelatter encompassing organic and inorganic acids, basis and buffers andnormally used in pharmaceutical compositions.

The pharmaceutical composition encompassing the compounds addressed bythis invention may also contain substances or be prepared with: (a)complexing agents to mask flavor, improve solubility, promote thesolubility of the formulation and/or modulate bioavailability, and (b)aromatizing and flavorizing agents used to correct or mask unpleasantodors and flavors, or to confer pleasant odors and flavors. Severalsubstances and preparations are available on the market for suchapplications, with their use being limited to approved agents, or thosethat have been duly certified, which are compatible with the ingredientsin the composition.

For therapeutic use and administration, the compounds addressed by thisinvention or its appropriate pharmaceutical salts may be formulated asset forth in compositions appropriate for oral, parenteral, nasal,rectal, transmucosal and transdermal administration, using conventionaltechniques and appropriate excipients. Thus, the compounds addressed bythis invention may be prepared as tablets, pills, capsules, dragées,granules, powders, pellets, aerosols, elixirs, solutions, lyophilizates,suspensions, syrups, suppositories and patches, among other known formsthat are appropriate for the administration pathways.

The therapeutic dose to be used of the compounds addressed by thisinvention must be planned and calculated in compliance with the selectedadministration pathway, the weight and condition of the patient and theseverity of the disorder being treated. In general, the compoundsaddressed by this invention are administered at therapeuticallyefficacious doses that vary from about 0.1 mg to about 1,000 mg per day,preferably 0.5 mg to 500 mg per day, but also preferably 1 mg to 250 mgper day, administered in a single or fractioned dose.

The determination of the activity of the synthesized compounds wasconducted through assays assessing affinity with the 5-HT_(1A) and5-HT_(2A) serotonin receptors. The assays used are based on the bindingratings of the substances being tested at different concentrations,compared to the affinity in the single concentration of the radioligands(markers) that have a specific affinity for these receptors.

These assays, known as binding assays and also known as inhibitionexperiments, are able to determine the affinity of a substance throughthe receptor, provided that this substance is soluble under the assayconditions.

In an inhibition experiment, the quantity of an inhibitor substance (nonradioactive—sample or compound being tested) included in the incubationis the only variable, meaning that it is possible to determine for eachtest drug concentration, the binding inhibition percentage of theradioligand.

CI₅₀ is a value defined as the concentration of an unbranded substance(test sample) required to inhibit the specific binding of theradioligand in 50% of the receptors.

The affinity assays with the 5-HT_(1A) and 5-HT_(2A) receptors of thecompounds addressed by this invention were conducted by the Biochemicaland Molecular Pharmacology Laboratory at the Biomedical ScienceInstitute in Rio de Janeiro Federal University (UFRJ), using its ownprotocols.

For the efficacy assay, the compounds addressed by this invention weresubmitted to the modified Irwin assay. The assays were conducted byPorsolt, using a specific protocol for evaluation.

Non-exhaustive examples are presented below that illustrate thepreparation of compounds addressed by this invention, the assays towhich they were submitted, and the results with comments on the affinitytests conducted on the 5-HT_(1A) and 5-HT_(2A) receptors and theefficacy test to which the compounds were submitted, demonstrating therelevance and usefulness of this invention.

EXAMPLES Example 1—Preparation of 3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one 1a.3-(2-hydroxyethyl)quinazoline-4 (3H)-one

A mixture of 2-aminobenzoic acid (2 g, 14.58 mmol), triethyl o-formate(6.07 mL, 36.4 mmol) and ethanolamine (0.94 ml, 15.54 mmol) wasmaintained in reflux for three hours. The reaction medium was cooled toroom temperature, adding 50 mL of water. The resulting suspension waskept in agitation at 15° C. for 4 hours and was then vacuum filtered.The raw product obtained was recrystalized ethanol yielding3-(2-hydroxyethyl)quinazoline-4 (3H)-one (2.5 g, yield=90%) as a whitesolid.

1b. 3-(2-chloroethyl)quinazoline-4 (3H)-one

This thionyl chloride (1,095 mL, 15 mmol) was added to3-(2-hydroxyethyl)quinazoline-4 (3H)-one (2.0 g, 10.52 mmol) in areactor, forming a white suspension that heated spontaneously to 85° C.The reaction medium was kept at this temperature under agitation forthirty minutes, after which it was left to cool to about 40° C. Next, 50mL of water was added, forming a pinkish suspension, which was keptunder agitation for two hours. The product was then vacuum filtered andwashed with three portions of 10 mL of an ethanol/water mixture (50%v/v), yielding 3-(2-chloroethyl) quinazoline-4 (3H)-one as a pale whitesolid (1.8 g, 8.63 mmol, yield=82%).

1c. 3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one

The following were added to a 250 mL reactor: 3-(2-chloroethyl)quinazoline-4 (3H)-one (1 g, 4.79 mmol), 1-(3-(trifluoromethyl)phenyl)piperazine (1,103 g, 4.79 mmol), sodium carbonate (0.762 g, 7.19 mmol),sodium iodide (0.072 g, 0.479 mmol), ethanol (50 ml) and toluene (150ml). The reaction medium was kept under agitation and reflux for aperiod of twenty hours, during which 150 ml of the solvent were removedslowly with the assistance of a Dean-Stark. To the resulting mixture,100 mL of an aqueous solution of acetic acid were added at 10% and 150mL of ethyl acetate. The mixture was agitated, the organic phaseseparated, washed with 2 portions of 50 mL of a 5% sodium bicarbonatesolution, dry with MgSO₄, filtered and evaporated to dryness, yieldingthe raw product as a slightly yellowish oil. This oil was dissolved inisopropanol, adding 2 mL of concentrated HCl under agitation to theresulting solution. This agitation was maintained for two hours in orderto complete the precipitation of the hydrochloride. The resulting solidwas filtered and vacuum dried, yielding 1.45 g of3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl) quinazoline-4(3H)-one hydrochloride (3.3 mmol, yield=69%).

Then 3-(2-(4-(3-(trifluoromethyl)phenyl) piperazine-1-yl)ethyl)quinazoline-4 (3H)-one in its base form was obtained from the rawproduct resulting from the treatment of the reaction medium, using thefollowing procedure:

5.0 g of raw 3-(2-(4-(3-(trifluoromethyl)phenyl) piperazine-1-yl) ethyl)quinazoline-4 (3H)-one isolated through the treatment of the reactionmedium was dissolved in 30 mL of isopropanol at 60° C. with agitation.The resulting solution was left to rest at a temperature of about 5° C.for a period of 12 hours to promote precipitation.

The resulting solid was vacuum filtered, washed with two portions of 10mL of isopropanol at 0° C. and dried, yielding the titered compound aswhite crystals (4.2 g; yield: 84%).

RMN ¹H (DMSO-d₆, 300 MHz): □3.25-3.72 (4H, m, (CH₂)₂), 3.25-3.98 (4H, m,(CH₂)₂), 3.61 (2H, br s, CH₂), 4.50 (2H, m, CH₂), 7.1 (1H, dd, J=1.9 and8 Hz), 7.3 (2H, m, (CH)₂), 7.5 (1H, m, (CH), 7.55 (1H, m, (CH), 7.7 (1H,dd, J=1.9 and 8.0 Hz, CH), 7.80 (1H, m, CH), 8.20 (1H, dd, J=1.9 and 8.0Hz, CH), 8.50 (1H, s, CH).

RMN ¹³C (DMSO-d₆, 300 MHz): □40.3 (1C, CH₂), 44.7 (2C, (CH₂)₂), 50.7(2C, (CH₂)₂), 53.8 (C1, CH₂), 111.6 (1C, CH), 112.2 (1C, CH), 119.2 (1C,CH), 120.8 (1C, qC), 122.4 (1C, CF₃), 126.0 (1C, CH), 126.1 (2C, CH),130.0 (1C, CH), 130.2 (1C, qC), 134.0 (1C, CH), 147.0 (1C, qC), 147.1(1C, CH), 149.8 (1C, qC), 160.0 (1C, C═O).

El-MS (70 ev): 402 [M]+, 243, 200, 172, 145, 102, 70

Example 2—Preparation of 3-(2-(4-o-tolylpiperazine-1-yl)ethyl)quinazoline-4 (3H)-one

This compound was prepared in compliance with the procedure described in1c, using 1-o-tolylpiperazine instead of1-(3-(trifluoromethyl)phenyl)piperazine.

RMN ¹H (DMSO-d₆, 300 MHz): □2.27 (3H, s, CH₃), 3.34 (2H, br s, CH₂),3.05-3.25 (4H, m, (CH₂)₂), 3.05-3.72 (4H, m, (CH₂)₂), 4.47 (2H, t, J=6.0Hz, CH₂), 7.01-7.20 (4H, m, (CH)₄), 7.58 (1H, dd, J=1.11 and 8.07 Hz,CH), 7.73 (1H, d, J=7.68 Hz, CH), 7.89 (1H, dd, J=1.5 and 7.17 Hz, CH),8.20 (1H, dd, J=1.23 and 8.01 Hz, CH), 8.48 (1H, s, CH).

RMN ¹³C (DMSO-d₆, 300 MHz): □17.4 (1C, CH₃), 40.0 (1C, CH₂), 48.1 (2C,(CH₂)₂), 51.9 (2C, (CH₂)₂), 54.0 (C1, CH₂), 118.9 (1C, CH), 121.5 (1C,qC), 123.7 (1C, CH), 124.0 (1C, CH), 126.0 (1C, CH), 126.6 (1C, CH),127.1 (1C, CH), 130.9 (1C, CH), 132.0 (1C, qC), 134.5 (1C, CH), 147.6(1C, CH), 147.8 (1C, qC), 149.5 (1C, qC), 160.7 (1C, C═O).

El-MS (70 ev): 348 [M]⁺, 215, 189, 146, 118, 92, 70

Example 3—Preparation of3-(2-(4-(2,3-dimethylphenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one

This compound was prepared in compliance with the procedure described in1c, using 1-(2,3-dimethylphenyl)piperazine instead of1-(3-(trifluoromethyl)phenyl)piperazine.

RMN ¹H (DMSO-d₆, 300 MHz): □2.17 (3H, s, CH₃), 2.22 (3H, s, CH₃), 3.34(2H, br s, CH₂), 3.05-3.64 (4H, m, (CH₂)₂), 3.05-3.72 (4H, m, (CH₂)₂),4.68 (2H, t, J=6.0 Hz, CH₂), 6.91 (2H, m, (CH)₂), 7.59 (1H, m, CH), 7.73(2H, m, (CH)₂), 7.85 (1H, m, CH), 8.20 (1H, m, CH), 8.48 (1H, s, CH).

RMN ¹³C (DMSO-d₆, 300 MHz): □14.7 (1C, CH₃), 21.3 (1C, CH₃), 40.0 (1C,CH₂), 49.7 (2C, (CH₂)₂), 53.1 (2C, (CH₂)₂), 55.2 (1C, CH₂), 117.8 (1C,CH), 122.7 (1C, qC), 126.8 (1C, CH), 127.0 (1C, CH), 127.2 (1C, CH),128.4 (1C, CH), 131.8 (1C, qC), 135.7 (1C, CH), 138.7 (1C, qC), 148.8(1C, qC), 149.0 (1C, CH), 150.8 (1C, qC), 162.0 (1C, C═O).

El-MS (70 ev): 362 [M]⁺, 217, 173, 147, 120

Example 4—Preparation of3-(2-(4-(2-chlorophenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one

This compound was prepared in compliance with the procedure described in1c, using 1-(2-chlorophenyl)piperazine instead of1-(3-(trifluoromethyl)phenyl)piperazine.

RMN ¹H (DMSO-d₆, 300 MHz): □3.18-3.35 (4H, m, (CH₂)₂), 3.18-3.73 (4H, m,(CH₂)₂), 3.63 (2H, br s, CH₂), 4.49 (1H, t, J=6.0 Hz, CH₂), 7.11 (1H, t,J=7.5 Hz, CH), 7.23 (1H, d, J=7.62 Hz, CH), 7.34 (1H, t, J=7.29 Hz, CH),7.46 (1H, d, J=8.3 Hz, CH), 7.58 (1H, m, CH), 7.72 (1H, d, J=8.07 Hz,CH), 7.89 (1H, t, J=7.29 Hz, CH), 8.20 (1H, d, J=7.71 Hz, CH), 8.48 (1H,s, CH).

RMN ¹³C (DMSO-d₆, 300 MHz): □40.0 (1C, CH₂), 47.5 (2C, (CH₂)₂), 51.6(2C, (CH₂)₂), 53.9 (1C, CH₂), 121.0 (1C, qC), 121.5 (1C, qC), 124.8 (1C,CH), 126.0 (1C, CH), 127.1 (1C, CH), 127.2 (1H, CH), 127.5 (1C, CH),128.2 (1C, CH), 130.4 (1C, CH), 134.4 (1C, CH), 147.7 (1C, CH), 147.8(2C, qC), 160.6 (1C, C═O).

El-MS (70 ev): 368 [M]⁺, 223, 209, 166, 159, 138, 111, 70

Example 5—Preparation of3-(2-(4-(2-cyanophenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one

This compound was prepared in compliance with the procedure described in1c, using 2-(piperazine-1-yl)benzonitryl instead of1-(3-(trifluoromethyl)phenyl)piperazine.

RMN ¹H (DMSO-d₆, 300 MHz): □3.65 (2H, br s, CH₂), 3.36-3.65 (4H, m,(CH₂)₂), 3.36-3.80 (4H, m, (CH₂)₂), 4.52 (2H, t, J=6.0 Hz, CH₂), 7.21(1H, m, CH), 7.28 (1H, m, CH), 7.56 (1H, m, CH), 7.65 (1H, m, CH), 7.72(1H, t, J=7.74 Hz, CH), 7.7 (1H, d, J=1.53 and 7.69, CH), 7.87 (1H, td,J=1.53 and 7.23 Hz, CH), 8.20 (1H, dd, J=1.2 and 7.98 Hz, CH), 8.58 (1H,s, CH).

RMN ¹³C (DMSO-d₆, 300 MHz): □40.8 (1C, CH₂), 44.0 (2C, (CH₂)₂), 50.5(2C, (CH₂)₂), 53.4 (1C, CH₂), 105.1 (1C, qC), 117.8 (1C, CH), 119.4 (1C,CH), 121.4 (1C, qC), 123.0 (1C, CEN), 126.0 (1C, CH), 126.8 (1C, CH),127.2 (1C, CH), 134.2 (1C, CH), 134.4 (1C, CH), 134.5 (1C, CH), 147.3(1C, qC), 147.8 (1C, CH), 153.3 (1C, qC), 160.5 (1C, C═O).

El-MS (70 ev): 359 [M]+, 217, 200, 159, 157, 129, 108, 70

Example 6—Preparation of3-(2-(4-(2-methoxyphenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one

This compound was prepared in compliance with the procedure described in1c, using 1-(2-methoxyphenyl)piperazine instead of1-(3-(trifluoromethyl)phenyl)piperazine.

RMN ¹H (DMSO-d₆, 300 MHz): □□3.50 (2H, br s, CH₂), 3.80 (3H, s, OCH₃),3.26-3.53 (4H, m, (CH₂)₂), 3.26-3.68 (4H, m, (CH₂)₂), 4.49 (1H, t, J=6.0Hz, CH₂), 6.92 (1H, m, CH), 6.96 (1H, m, CH), 7.00 (1H, d, J=8.0 Hz,CH), 7.04 (1H, d, J=8.0 Hz, CH), 7.58 (1H, dd, J=1.53 and 8.13 Hz, CH),7.72 (1H, d, J=8.0 Hz, CH), 7.86 (1H, td, J=1.53 and 8.13 Hz, CH), 8.18(1H, dd, J=1.1 and 7.98 Hz, CH), 8.50 (1H, s, CH).

RMN ¹³C (DMSO-d₆, 300 MHz): □□40.0 (1C, CH₂), 46.7 (2C, (CH₂)₂), 51.5(2C, (CH₂)₂), 53.8 (1C, CH₂), 55.3 (1C, OCH₃), 111.9 (C1, CH₂), 118.9(C1, CH₂), 120.8 (1C, qC), 121.5 (C1, CH), 123.4 (C1, CH), 126.0 (C1,CH), 127.0 (C1, CH), 127.1 (C1, CH), 134.4 (C1, CH), 139.3 (1C, qC),147.6 (1C, CH), 147.8 (1C, qC), 151.8 (1C, qC), 160.6 (1C, C═O).

El-MS (70 ev): 364 [M]⁺, 217, 205, 191, 162, 143, 120, 93, 70

Example 7—Preparation of 2-ethyl-3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one 7a.2-ethyl-4H-3,1-benzoxazin-4-one

Propanoyl chloride (6.2 g, 67 mmol) was added to a solution ofanthranilic acid (1 g, 7.3 mmol) in dichloromethane (20 mL). Thereaction medium was kept under reflux and agitation, with the end of thereaction being monitored by CG/MS. After the end of the reaction, ahydrochloric acid solution was added (20 mL, 1M), and the resultingmixture was extracted with ethyl acetate (100 mL), the extract was driedwith magnesium sulfate and the solvent was evaporated. Acetic anhydride(15 mL) was added to the residue and the reaction medium was taken toreflux and accompanied through CG/MS in order to monitor cyclization.After the end of the reaction, the reaction medium spin dried at atemperature of 65° C. using portions of toluene to facilitate theelimination of the anhydride. 1.0 g of the raw product2-ethyl-4H-3,1-benzoxazin-4-one was obtained, which was used directly inthe stage subsequent to reaction.

7b. 2-ethyl-3-(2-hydroxyethyl) quinazoline-4 (3H)-one

1 g of 2-ethyl-4H-3,1-benzoxazin-4-one was added to 10 mL ofmonoethanolamine and the mixture was heated to 100° C. for 40 minutes.The heating element was then removed and the reaction medium was keptunder agitation for about eight hours (end of the reaction). 100 mL wereadded to the reaction medium and the mixture was extracted with threeportions of 25 mL of ethyl acetate. The organic phase was separated, anddried with magnesium sulfate and spin dried, yielding the2-ethyl-3-(2-hydroxyethyl)quinazoline-4 (3H)-one compound as a yellowishoil, which solidified when left to rest at room temperature, which wasused in the next stage, with no purification.

Yield: 0.95 g (76%)

7c. 3-(2-chloroethyl)-2-ethylquinazoline-4 (3H)-one

2-ethyl-3-(2-hydroxyethyl) quinazoline-4 (3H)-one (5.00 g; 22.91 mmol)and thionyl chloride (1.672 mL, 22.91 mmol) were added to a 150 mLreactor, together with 60 mL of chloroform. The reaction medium washeated to reflux and for completing the reaction, which was accompaniedthrough CG/MS. After the end of the reaction, 100 mL of hexane wereadded and the solution was agitated at room temperature in order toprecipitate the product. The resulting suspension was vacuum filtered,washed with two portions of hexane and dried, yielding3-(2-chloroethyl)-2-ethylquinazoline-4 (3H)-one as a white solid (1.78g; 7.52 mmol; yield: 32.8%).

7d. 2-ethyl-3-(2-(4-(3-(trifluoromethyl)phenyl) piperazine-1-yl)ethyl)quinazoline-4 (3H)-one

3-(2-chloroethyl)-2-ethylquinazoline-4 (3H)-one (1.5 g; 6.34 mmol),1-(3-(trifluoromethyl)phenyl)piperazine (1.459 g; 6.34 mmol), sodiumcarbonate (0.672 g; 6.34 mmol), sodium iodide (0.95 g; 6.34 mmol),ethanol (100 mL) and toluene (200 mL) were added to a 100 mL reactor.The reaction medium was heated to reflux and kept under agitation for aperiod of 24 hours, during which 250 mL of solvent were slowly removedwith assistance from a Dean Stark. The reaction was monitored throughCG/MS until completion. After the end of the reaction, ethyl acetate(250 mL) was added, together with an aqueous solution of acetic acid(100 mL; 10%). The mixture was maintained under agitation for a periodof 30 minutes. The organic phase was separated, washed with two portionsof 50 mL of NaHCO₃ at 5%, dried with MgSO₄ and evaporated at reducedpressure, yielding a pale yellow colored oil (2.7 g of raw2-ethyl-3-(2-(4-(3-(trifluoromethyl) phenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one). This oil was dissolved in isopropanol, adding2.0 mL of concentrated HCl to the resulting solution. The solution waskept under agitation at room temperature, until completing precipitationof the solids. The solids were vacuum filtered, washed with two portionsof 5 mL of isopropanol and dried, yielding2-ethyl-3-(2-(4-(3-(trifluoromethyl)phenyl)piperazine-1-yl)ethyl)quinazoline-4 (3H)-one hydrochloride as a pale white solid (2.36 g, 5.48mmol, yield: 87%).

The 2-ethyl-3-(2-(4-(3-(trifluoromethyl) phenyl) piperazine-1-yl)ethyl)quinazoline-4 (3H)-one was prepared through dissolving the isolated rawproduct in oil, as described above, through dissolving it in boilingisopropanol, followed by cooling to room temperature, then leaving it at5° C. for a period of 12 hours, during which the product precipitated.

RMN ¹H (DMSO-d₆, 300 MHz): □□1.34 (3H, t, J=6.96 Hz, CH₃), 3.03 (2H, dd,J=6.75 and 13.86 Hz, CH₂), 3.29-3.75 (4H, m, (CH₂)₂), 3.29-4.00 (4H, m,(CH₂)₂), 3.48 (2H, br s, CH₂), 4.5 (2H, m, CH₂), 7.17 (1H, d, J=7.35 Hz,CH), 7.3 (2H, d, J=9.48 Hz, (CH)₂), 7.5 (2H, m, CH), 7.6 (1H, m, CH),7.82 (1H, m, CH), 8.13 (1H, d, J=7.74 Hz, CH).

RMN ¹³C (DMSO-d₆, 300 MHz): □10.8 (1C, CH₃), 27.2 (1C, CH₂), 40.0 (1C,CH₂), 44.7 (2C, (CH₂)₂), 50.6 (2C, (CH₂)₂), 52.0 (C1, CH₂), 111.6 (1C,CH), 115.7 (1C, CH), 119.2 (1C, CH), 119.7 (1C, qC), 122.5 (1C, CF₃),126.0 (1C, CH), 126.4 (1C, CH), 126.7 (1C, CH), 130.1 (1C, qC), 130.2(1C, CH), 134.5 (1C, CH), 146.0 (1C, qC), 146.7 (1C, qC), 149.8 (1C,qC), 161.3 (1C, C═O).

El-MS (70 ev): 430 [M]⁺, 256, 243, 200, 172, 145, 116, 70

Example 8—Preparation of 3-(2-(4-(2,3-dimethylphenyl)piperazine-1-yl)ethyl)-2-ethylquinazoline-4 (3H)-one

This compound was prepared in compliance with the procedure described in7d, using 1-(2,3-dimethylphenyl)piperazine instead of1-(3-(trifluoromethyl)phenyl)piperazine.

El-MS (70 ev): 390 [M]⁺, 203, 187, 160

Example 9—Preparation of 2-ethyl-3-(2- (4- (2-methoxyphenyl)piperazine-1-yl)ethyl) quinazoline-4 (3H)-one

This compound was prepared in compliance with the procedure described in7d, using 1-(2-methoxyphenyl)piperazine instead of1-(3-(trifluoromethyl)phenyl)piperazine.

El-MS (70 ev): 392 [M]⁺, 205, 187, 162

Example 10—Preparation of 2-ethyl-3-(2-(4-(2-ethoxyphenyl)piperazine-1-yl)ethyl) quinazoline-4 (3H)-one

This compound was prepared in compliance with the procedure described in7d, using 1-(2-ethoxyphenyl)piperazine instead of1-(3-(trifluoromethyl)phenyl)piperazine.

El-MS (70 ev): 406 [M]⁺, 219, 187, 176

Example 11—Preparation of3-(2-(4-(2-chlorophenyl)piperazine-1-yl)ethyl)-2-ethylquinazoline-4(3H)-one

This compound was prepared in compliance with the procedure described in7d, using 1-(2-chlorophenyl)piperazine instead of1-(3-(trifluoromethyl)phenyl)piperazine.

El-MS (70 ev): 396 [M]⁺, 223, 200, 195, 173

In vitro affinity assays—5HT_(1A) and 5-HT_(2A) receptors

The affinity assays with the 5-HT_(1A) and 5-HT_(2A) receptors for thecompounds addressed by this invention were conducted by the Biochemicaland Molecular Pharmacology Laboratory at the Biomedical ScienceInstitute in Rio de Janeiro Federal University (UFRJ), using its ownprotocols. The development of the experiment protocol to assesscompounds with affinity for the 5-HT_(1A) receptors was developed on thebasis of the experiments conducted by Hall et al (Journal ofNeurochemistry (1985) 44: 1685-1696); Mongeau et al (Brain Research(1992) 590: 229-238) and Peroutka (Journal of Neurochemistry (1986) 47:529-540). The 5-HT_(2A) receptors were based on the studies conducted byJohnson et al (Naunyn-Schmiedeberg's Arch. Pharmacol. (1996) 354 (2):205-209); Leysen et al (Molecular Pharmacology (1982) 21: 301-314) andNelson et al (Journal of Pharmacology and Experimental Therapeutics(1993) 265: 1272-1279).

The affinity with the 5-HT_(1A) receptors was assayed by using3[H]-8-OH-DPAT (3[H]-8-hydroxy-N,N-dipropyl-2-aminotetraline) (1 nM) asa ligand, and 5-HT (5-hydroxytiptamine-serotonin) (10 μM) as anon-specific ligand. The assay tissue was rat hippocampus.

In order to determine the affinity with the 5-HT_(2A) receptors,3[H]-ketanserin (1 nM) was used as a ligand and ketanserin (1 μM) as anon-specific ligand. The assay tissue was rat cortex. The findings forthe affinities are summarized in Tables 1 and 2 below. Table 1 belowsummarizes the C150 values obtained for the inventive compoundspresented in Examples 1 and 8. In order to determine the CI₅₀ of thesecompounds, the inhibition assays were conducted using the compounds atconcentrations of 3, 10, 30, 100, 300, 1000 and 3000 nM (in duplicate)for both receptors.

TABLE 1 Determination of the CI₅₀ Values. 5-HT_(1A) 5-HT_(2A)5-HT_(2A)/5-HT_(1A) Compounds CI₅₀ (nM) CI₅₀ (nM) CI_(502A)/CI_(501A)Example 1 47 570 12 Example 7 253 707 2.7 Comparative 47 453 9.6Compound * *1,3-Dihydro-1-(2-(4-(3-(trifluoromethyl)phenyl)-1-piperazinyl)ethyl)-2H-benzimidizol-2-one(Flibanserin)

Pursuant to the data presented in Table 1, the inventive compoundaddressed in Example 1 presented the same CI₅₀ value as the comparativecompound constituting the state of the art for the 5-HT_(1A) receptor.For the 5-HT_(2A) receptors, the inventive compound addressed in Example1 presented a value slightly higher than the value obtained for thecomparative compounds.

The compound addressed in Example 7 presented a C150 value some fivetimes greater for the 5-HT_(1A) receptors. However, for the 5-HT_(2A)receptors, this compound presented greater affinity than the comparisoncompound and the compound in Example 1. Although presenting lessaffinity for the 5-HT_(1A), receptor, this compound demonstrated that itwould be interesting as it presented a lower 5-HT_(2A)/5-HT_(1A) ratioof interaction on these receptors.

Table 2 presented below summarizes the findings obtained for determiningthe affinities of the other compounds addressed by this invention. Thevalues presented in the Tables correspond to the assay concentrations ofthe compounds and the respective inhibition percentages noted.

TABLE 2 Inhibition Percentages 5-HT_(1A) 5-HT_(2A) Inhibition PercentageInhibition Percentage 30 100 300 300 1000 3000 Compounds nM nM nM nM nMnM Example 2 21 51 — 61 82 — Example 3 47 84 — 89 88 — Example 4 22 84 —48 77 — Example 5 12 49 — 38 78 — Example 6 38 66 — 43 63 — Example 8 2676 77 67 86 94 Example 9 17 46 69 13 46 78 Example 10 26 51 79 8 27 58Example 11 5 26 38 25 52 79

In Vivo Efficacy Test

In order to determine the in vivo efficacy of the compounds addressed bythis invention, the Serotonin Syndrome Model in rats was used. The modelwas based in the Irwin method (Psychopharmacologia (1968), 13: 222-257),adapted to assess the effects of seroton agonists pursuant to Martin etal (Journal of Pharmacol. Meth. (1985), 13: 193-200) and Ortman et al(Naunyn-Schmiedeberg's Arch. Pharmacol (1981), 316: 225-230).

In the experiment, the compounds being tested were administered to rats(N=6 per group) which were observed in simultaneous comparison with acontrol group, to which only the excipient was administered astreatment. Two animals from each group were assessed through a series ofseparate observations. Escitalopram was used as the positive control forthe study.

Behavioral and physiological alterations as well as neurotoxicitysymptoms, rectal temperature and pupil diameter were recorded.

Additionally, the specific signs related to the stimulation of the 5-HTreceptors were observed and quantified, being: head twitches (HT), forepaw treading (FPT), flat body posture (FBP), hind limb splay (HLS),lower lip retraction (LLR) and spontaneous tail flicks (STF) (Straub).

The observations were conducted at 15, 30 and 60 minutes afteradministration of the compounds being tested.

The compounds were tested as set forth in Examples 1 and 7. As thecomparative compound1,3-dihydro-1-(2-(4-(3-(trifluoromethyl)phenyl)-1-piperazinyl)ethyl)-2H-benzimidizol-2-one (Flibanserin) was used. All the compoundswere administered at a dose of 15 mg/kg, intraperitoneal.

The observations of the specific stimulation data of the 5-HT receptorsby each compound are presented in the graph given in FIG. 1.

At this dosage, it was possible to note that the compounds presented inExamples 1 and 7 triggered signs of stimulations of the 5-HT receptors.For the compound addressed in Example 1 triggered spontaneous tailflicks (STF), while the compound addressed in Example 7 triggered forepaw treading (FPT) and more spontaneous tail flicks (STF). These twoeffects are usually triggered by substances that act as 5-HT_(1A)receptor agonists, with their expressions usually attributed to thepost-synaptic activation of these receptors. Among the animals testedwith the comparison compound constituting the state of the art of thisconcentration, only one presented signs of stimulation of the 5-HTreceptors, which were spontaneous tail flicks.

Although used as therapeutic doses equivalent to those for thecomparison substance constituting the state of the art, the compoundsaddressed by this invention demonstrated greater strength and efficacywhen used at the same therapeutic concentration. As these compoundspresent similar molecular weight, with the lowest molecular weight beingthat of the comparison compound, this difference may not be simplyattributed to the possible the possible molar concentrations employed.If the findings obtained in the in vitro affinity tests are considered,with the 5-HT_(1A) and 5-HT_(2A) receptors, the difference in theeffects achieved for the compounds addressed in Examples 1 and 7 areeven more striking and unexpected, I contrast to the comparisoncompound, especially for the compound addressed in Example 7, whose CI₅₀levels are higher than those obtained for the other compounds. Among thehypotheses that might explain this significant activity is the greaterpower to reach the central nervous system with highly efficaciouspermeation of the hematoencephalic barrier, or perhaps its activity isdue to the lower ratio between the CI₅₀ (5-HT_(2A)/5-HT_(1A)), orpossibly a combination of these factors might be responsible fortriggering this surprisingly strong effect.

1. A 5-HT1A and 5-HT2A serotonin modulator compound having the formula(I):

wherein: n=2, R1 is hydrogen, and R2 is 2-methoxyphenyl; orpharmaceutically acceptable salts thereof.
 2. A pharmaceuticalcomposition comprising the compound according to claim 1 and apharmaceutical acceptable excipient.
 3. The pharmaceutical compositionaccording to claim 2, wherein the compound in the composition is in anamount sufficient to treat a disorder associated with the 5-HT_(1A) and5-HT_(2A) receptors in a patient.
 4. The pharmaceutical compositionaccording to claim 3, wherein a dosage of the compound is an amount offrom about 0.1 mg to about 1,000 mg.
 5. The pharmaceutical compositionaccording to claim 4, wherein the dosage is from about 5 mg to about 500mg.
 6. The pharmaceutical composition according to claim 4, wherein thedosage is from about 1 mg to about 250 mg.
 7. The pharmaceuticalcomposition according to claim 3, wherein the composition is in a formthat is suitable for administration via a mode selected from the groupconsisting of oral, parenteral, nasal, rectal, transmucosal, andtransdermal administration,
 8. The pharmaceutical composition accordingto claim 3, wherein the disorder associated with the 5-HT_(1A) and5-HT_(2A) receptors is selected from the group consisting of depression,anxiety, phobias, panic, addictions, aggressiveness, impulsiveness,eating disorders, sleep disorders, obsessive-compulsive disorder,psychotic disorders, disorders involving the heat regulation mechanism,female sexual dysfunctions, hypoactive sexual desire disorder, sexualaversion disorder, female sexual excitation disorder, and the loss,inhibition or absence of sexual desire.